Quaternary ammonium group-containing polymers having antimicrobial activity

ABSTRACT

Polymeric quaternary ammonium compounds having recurring vinylbenzyl ammonium units are disclosed. The quaternary ammonium units preferably have 2 alkyl substituents of 1 to 4 carbons and 1 alkyl substituent of 4 to 12 carbons. These materials have antimicrobial properties and are particularly useful for preserving ophthalmic solutions.

This application is a continuation of application Ser. No. 302,684 filedSept. 15, 1981, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to quaternary ammonium group-containing polymers.More particularly it concerns a family of such polymers that exhibitantimicrobial activity and their application as antimicrobials.

2. Prior Art

Quaternary ammonium group-containing polymers have been widely studied.A review of the literature has turned up a vast collection of referencesto the general subject. As this invention relates to quaternary ammoniumpolymeric compounds having antimicrobial activity as well as to certainnew copolymeric quaternary polymers, three references to Green et al.may be of interest. These references, U.S. Pat. Nos. 3,931,319;4,005,193; and 4,025,617, disclose polymeric quaternary ammoniumpolymers having antimicrobial activity. However, Green et al.'s polymersare structurally dissimilar to the present materials.

The polymers of the invention may be classified as having apoly(vinylbenzyl quaternary ammonium) halide structure. In certainembodiments, they have a copolymer structure with repeating ##STR1## X⁻=physiologically acceptable anion R's=alkyls

q=1 to 4, preferably 2 units.

U.S. Pat. Nos. 2,702,795 of Gilwood; 2,772,310 of Morris; 3,563,949 ofHartenstein and 4,087,599 of Roe et al., as well as Journal of PolymerScience, Polymer Chemistry Edition, Vol. 18, pp. 455-65, 619-80, Draganet al., are certainly of interest as they show similar groups but do notsuggest the present materials.

These polymeric quaternary compounds fill a well indentified andrecognized need for a polymeric antimicrobial agent similar to orsurpassing known nonpolymeric species such as hexachlorophene, Zephiran®and the like. Being large polymeric molecules, the present materials areless mobile and less likely to migrate or inappropriately penetrate orbe absorbed into substrates. This permits their use in environmentswhere penetration or displacement or volatilization are problems.Further, it permits residual antimicrobial activity to be imparted tosurfaces and the like by the use of these materials.

STATEMENT OF THE INVENTION

It has now been discovered that polymeric quaternary amines havingrecurring vinylbenzyl ammonium groups of the structure ##STR2## whereinR is a 4 to 12 carbon atom alkyl and R' and R" are each independently 1to 4 carbon atom alkyls and X⁻ is an anion such as halide, haveantimicrobial activity. Such materials can be homopolymers butpreferably are copolymers. These polymers and copolymers constituteaspects of this invention. Antimicrobial compositions based on them andtheir use constitute additional aspects.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term "recurring" when used herein to describe mer units of a polymeris an inclusive term to describe homopolymers and copolymers with orwithout added copolymer units.

Molecular weights are expressed in daltons (D) and are determined by gelpermeation chromatography comparison of experimental compounds withchemically similar standards of known molecular weight.

Weights, temperatures and pressures are given in metric units unlessotherwise noted.

"Hygienically acceptable" refers to the property of being acceptable asa component of a material to be used to clean, disinfect or sterilize ahuman's or animal's physiological environment.

"Physiologically acceptable" means non-toxic and usable in materialscontacting or consumed by mammals including man.

"Mer unit" means a discrete repeating unit within the polymer structure.

The Quaternary Ammonium Repeat Unit

The homopolymers and copolymers of this invention always contain avinylbenzyl ammonium salt as a recurring mer unit. This unit has thestructure ##STR3## wherein R is a 4 to 12 carbon alkyl and R' and R" arethe same or different 1 to 4 carbon atom alkyls. X is a physiologicallyacceptable anion. Preferably R is a 6 to 10 carbon atom linear orbranched alkyl--i.e. hexyl, 2-ethylhexyl, octyl, decyl, nonyl, heptyl,2,4-dimethylhexyl and the like. Also preferably R' and R" are 1 to 2carbon atom alkyls--that is methyl or ethyl. Usually and morepreferably, R' and R" are the same alkyl. The more preferred arrangementhas R equal to an about 8 carbon atom alkyl. Most preferably R isn-octyl and R' and R" are each methyl.

Counterion X⁻ may be any physiologically acceptable anion. However,usual preparative methods generally lead to a halide (e.g. Cl³¹, I⁻ orBr⁻) with chloride ion being by far the most common.

Copolymeric Units

Optionally and preferably the polymers contain copolymeric units--hereinthe generic structure being depicted as --CU--. The units can be addedfor such down-to-earth purposes as to reduce the average cost per unitweight of the polymer or to "dilute" the active units and thus yield amore easily measured, handled or applied material. The copolymeric unitscan be added to achieve or enhance desired physical properties, as well.Such properties included greater antimicrobial activity, bettersolubility in aqueous or nonaqueous media, better miscibility in variousmedia, enhanced dispersibility, enhanced film forming and the like.

The first type of "CU" units are represented by styrene and similarvinylaromatics and lower alkenes or alkadienes such as ethylene,butadiene and the like. The second type of CU units are illustrated byvinyl acetamide, vinyl amine, vinyl amine quaternized withhydroxyethylenes or similar water solubilizers or with hydrophobes suchas dodecyls, or vinylbenzyl amine quaternized with three long chainalkyl hydrophobes or with three lower alkyl or hydroxyalkyl hydrophiles.Other units include for example vinyl acetate, vinyl alcohol, acrylicacid, acrylate and methacrylate esters; acrylamide and acrylamidederivatives including quaternized acrylamide; N-vinylimidazole andderivatives thereof including quaternized N-vinylimidazoles;4-vinylpyridine and derivatives thereof including quaternized4-vinylpyridines; N-vinylpyrrolidone and derivatives thereof;vinylbenzyl ethers of polyethylene glycols and their monoalkyl ethers.These units are all known in the art as are the methods for theirincorporation into copolymers. Mixtures of two or more CU units may, ofcourse, be used.

Generically, the CU's can be grouped as 2 to 6 carbon alkylenes oralkenylenes having pendent therefrom from 0 to 2 inclusive substitutentgroups selected from aryls, alkaryls, and aralkyls of 6-8 carbons,alkyls of 1-4 carbons, amides, hydroxyls, carboxylic acids, and theiresters, nitrogen-containing 5 or 6 atom heterocyclics and amine andether-substituted aryls, alkaryls, and aralkyls.

One preferred group of copolymer units are vinylbenzyl aminesquaternized by hydrophilic groups such as hydroxyalkyls of from 1 to 4carbon atoms, particularly vinylbenzyl amines quaternized with three2-hydroxyethylenes (i.e. with a triethanolamine structure). Such unitsare represented structurally as ##STR4## wherein q is 2 through 4inclusive and most preferably 2.

Another preferred group of copolymer units are vinylbenzyl ethers ofpoly(ethylene glycol)s or their monoalkyl ethers, particularly methylethers. Such units are represented structurally as ##STR5## wherein y is1 through 10 inclusive, preferably 1 through 4 inclusive, and R"' is ahydrogen or lower alkyl unit, such as from 1 to 4 carbons most generallymethyl.

Molecular Size and Proportions of Units

The polymeric quaternary amines of this invention have at least about 10mer units on average in each polymer molecule. Preferably they containfrom 10 to about 2000 mer units. This gives rise to molecular weightsfor the homopolymer of from about 3000 to about 600,000 and forcopolymers, of from about 1000 to a million or so, depending upon theunit and proportions employed. More preferably the number of mer unitsis from about 20 to about 1000.

The proportion of copolymeric mer units in the polymer can vary from 0(homopolymer) to about 90% of the total. Among copolymers, those havingat least about 20% of copolymer unit (CU's) are generally preferred.With less than this level, often the products have essentially theproperties of the homopolymer.

This means that structurally the polymers can be represented as follows:##STR6## wherein R is a 4 to 12 carbon atom alkyl and R' and R" are 1 to4 carbon alkyls and n is 10 to 2000 and X is an anion; and wherein theR's and X and n are as set forth, m+p=n, p=0 to 0.9(n) preferably 0.2 to0.9(n) and CU is a copolymeric unit.

The two preferred families of copolymers are represented by ##STR7##wherein m+p=n, q is 2 through 4 inclusive, and the R's and X⁻ are asdefined; and especially when R is octyl and R' and R" are each methyls,q is 2 and n is 20 to 100 and p is about 0.3 n; and ##STR8## wherein m,p, X⁻ and R, R', and R" are as defined and y is 1 to 10 preferably 1through 4 inclusive and R"' is hydrogen or lower alkyl of 1 through 4carbons, especially methyl.

Preparation of the Polymers

The polymers of this invention can be prepared by the general processof:

a. polymerizing vinylbenzyl halide plus any optional comonomer unitsusing free-radical catalysis, and

b. reacting the resulting poly(vinylbenzyl halide) with tertiary amineto yield the desired quaternary amine which is thereafter recovered.

In a representative preparation, the polymerization reaction is carriedout with the monomer(s) in solution in an inert organic, often aromaticreaction medium such as toluene, benzene, tetrahydrofuran, ormethylethyl ketone. It is of advantage to have an inert atmosphere, suchas argon, over the reaction zone. A free-radical initiator such as aperoxide, or for example, AIBN (azobisisobutyronitrile) is employed inamounts of from 0.01 to 0.5% wt (basis monomer). The reaction is carriedout at elevated temperatures, for example at temperatures of from 50° to150° C., most commonly at the reflux temperature of the reaction medium.Elevated pressures may be employed to achieve temperatures aboveatmospheric reflux. The reaction takes a substantial period-often aslong as several days. Of course, this period is related to thetemperature employed with higher temperature requiring shorter time andlower temperature requiring longer times. As a guideline, at 75°-80° C.reaction temperature the reaction is complete in 18 to 24 hours. Thepolymeric intermediate product is recovered such as by precipitationfollowing nonsolvent addition. The molecular weight of the resultingpolymer can be varied by changing reaction conditions, such as themonomer and free radical initiator concentrations, solvent composition,and the reaction temperature as is known in the art.

The coupling of the tertiary amine to the poly(vinylbenzyl halide) iscarried out in a relatively polar organic solvent system such as THF oralkanols or mixtures thereof. Examples of such solvent systems aretetrahydrofuran (THF), methanol, ethanol, isopropanol, isobutanol,THF:ethanol, THF:isopropanol, and THF:isobutanol. A preferred solventsystem is 1:1 THF:isopropanol.

The reaction is carried out by admixing the poly(vinylbenzyl halide) andthe tertiary amine in the reaction medium and heating. The amount oftertiary amine should be controlled. If a homopolymer product isdesired--i.e. with all available benzyl halide groups reacted--it is ofadvantage to add an excess of amine, such as from about 1.0 to 1.5 ormore equivalents of amine per mole of available benzyl halide. Theexcess is employed only to speed the reaction. In fact, the amine willreact relatively quantitatively with available halide sites. Thus, whenit is desired to react only a portion of the available halide sites withtertiary amine, less tertiary amine should be added. For example, when a1:1 equivalent tertiary amine:trialkanol amine copolymer is desired, onegenerally adds about 0.5 equivalent of trialkyl amine, basis availablesites.

This reaction is complete in 24 hours at 60°-80° C. The reactants arerelatively heat stable so higher temperatures such as up to 150° C. canbe employed without adversely affecting the reaction's yield. Thustemperatures from about 50° to 150° C. and times of 1 to 24 hours can beemployed with temperatures of 60° to 140° C. being preferred.

Other reactants with the benzyl halide sites, for exampletrialkanolamines, can be added together with the trialkylamine orsequentially. If two materials are added at the same time, one must becareful not to add an excess of the more reactive material or else thereaction will not give the stoichiometry desired. Usually two materialsare added sequentially. The coupling of the second material may becarried out in the same reaction medium without intermediate isolationof the product. The coupling of the second material generally employssimilar reaction conditions to those used to couple the first.

After coupling, it is desirable to purify the final product to removeexcess amines, salts and the like. Dialysis, ultrafiltration and otherart-known processes for isolating and purifying polymers can beemployed.

Formulation of Antimicrobial Compositions

The polymers of this invention are characterized as having antimicrobialactivity. In this use they are formulated into antimicrobialcompositions such as by being admixed with an hygienically acceptablecarrier or vehicle.

This antimicrobial activity gives the materials utility as preservationsfor ophthalmic solutions, especially wetting solutions, cleaningsolutions, cushioning solutions and soaking solutions for hard and softcontact lenses. In the case of soft contact lenses, the materials offera special advantage of not absorbing and concentrating within the lensas monomeric antimicrobials and preservatives have been known to do.Other utilities are as preservations and/or antimicrobials for haircare, and topical pharmaceutical products. Other uses includeincorporation in intra-vaginal anti-infectives, spermicides, therapeuticskin care (anti-acne) preparations and use as persistent deodorants orantimicrobials for body cavities such as the abdomen, lungs, or GI tractand the like. In addition, the products can be formulated with variouscleanser components to form persistent disinfectants for home orhospital use.

In these applications, the products are generally admixed with asuitable carrier or medium such as sterile water or saline, gel salvebases, and the like in an antimicrobially effective amount--which amountis defined to be an amount sufficient to effect the desiredantimicrobial or preserving action. Such amounts vary from as little as10-20 ppm to as much as 1000 ppm (in finished product form) or up to 5%in concentrated formulations.

The amount employed will also vary somewhat depending upon the exactmaterial employed. The most active materials appear to be those having adimethyl-n-octyl ammonium salt configuration. Interestingly, as oneincreases or decreases the "long" group chain length say to C₄ or C₁₂the activity falls off. At the "trimethyl" or "dimethyloctadecyl"extremes, antimicrobial activity is essentially absent. In generalterms, this activity is as shown in Table 1.

                  TABLE I                                                         ______________________________________                                                     Antimicrobial Activity                                           Compound     (relative units)                                                 ______________________________________                                        R = C.sub.2  0.0                                                              C.sub.4      0.1                                                              C.sub.6      0.8                                                              C.sub.8      1.0                                                              C.sub.10     0.8                                                              C.sub.12     0.2                                                              C.sub.18     0.1                                                              ______________________________________                                    

The antimicrobial formulations are prepared by conventional means ofadmixing, grinding and the like. In this regard, the polymers can beconsidered to be like other water-soluble salts and may be treatedaccordingly. No special formulation techniques are usually required.

The invention will be further described by the following examples. Theseare provided for purposes of illustration and are not to be consideredas limiting the invention's scope.

EXAMPLE I A. Preparation of Poly(chloromethylstyrene)

AIBN (3.8 g, 23.1 mmoles) and 100 ml of toluene were charged to amagnetically-stirred reactor flask. Then 152.5 g (1.00 mole) ofchloromethylstyrene was added with toluene to give a 900 ml reactionvolume. Argon gas was bubbled through the mixture and it was heated inan oil bath to 78°-80°. It was stirred for 22 hours at this temperatureand then cooled.

The polymer was recovered by adding hexane and dropping the mixture into1.5 l of hexane. A taffy-like precipitate formed, was collected, wasrinsed in water, redissolved in THF, filtered, precipitated in petroleumether, redissolved in THF and finally precipitated in methanol. Theprecipitate was collected and vacuum dried for nine hours at 60° C. Theproduct was a powder having an average molecular weight by gelpermeation chromatography comparison with polystyrene of 6.4×10³.

B. Coupling of Trialkyl Amine

A solution of poly(chloromethylstyrene) (prepared in step A); (1.52 g,10 mmole) in 50 ml of a one-to-one mixture of tetrahydrofuran andisopropanol was heated to reflux with stirring. Dimethyloctylamine (1.14g, 7.25 mmole) was added and the reaction mixture was refluxed for 24hours. This yielded the partially substituted poly(chloromethylstyrene)of the average formula ##STR9## This product was not isolated. Theentire reaction product was employed in step C.

C. Addition of Trialkanolamine

Triethanolamine (2.0 g, 13.4 mmole) was added to the reaction product ofPart B, followed by 30 ml of isopropanol. The reaction mixture was thenrefluxed another 24 hours. At the conclusion of this reaction period,the homogenous mixture was cooled, diluted to three times its originalvolume with water, and the volatile constituents removed by in vacuodistillation (rotary evaporator). The residue, after concentration toone-half volume, was diluted with three volumes of 20% aqueousisopropanol and ultrafiltered through a 10,000 molecular-weight-cutoffcartridge (Amicon H1P10) with ten diavolumes of deionized water. Theretentate was then concentrated by ultrafiltration to 100 ml andlyophilized to yield 2.46 g fluffy white solid of the formula ##STR10##

A solution of polychloromethylstyrene of Part A, Example I (1.52 g, 10mmole) in 50 ml of one-to-one mixture of tetrahydrofuran and isopropanolwas heated to reflux with stirring. Dimethyl hexylamine (1.42 g, 11mmole) was added and the reaction mixture was refluxed 18 hours. Aftercooling, the homogeneous reaction mixture was diluted with water tothree times its original volume, and the volatile constituents removedby distillation in vacuo (rotary evaporator). The residue afterconcentration by one-half was diluted with three volumes of water andultrafiltered with deionized water (ten diavolumes) using a 10,000molecular weight cutoff cartridge (Amico H1P10). Lyophilization afforded2.6 g of fluffy white solid of the formula ##STR11##

EXAMPLES III-VI and Comparative Experiments 1 and 2

The preparation of Example I was repeated substituting fordimethyloctylamine in equivalent amounts as follows:

    ______________________________________                                        Comparative Experiment 1                                                                         trimethylamine                                             Comparative Experiment 2                                                                         dimethylethylamine                                         Example III        dimethyl-n-butylamine                                      Example IV         dimethyl-n-hexylamine                                      Example V          dimethyl-n-decylamine                                      Example VI         dimethyl-n-dodecylamine                                    Example VII        dimethyltetradecylamine                                    Example VIII       dimethylhexadecylamine                                     Comparative Experiment 3                                                                         dimethyloctadecylamine                                     ______________________________________                                    

Additional Illustrative Embodiments (A-O)

The preparations of Examples I and II are each repeated four times withthe following changes:

A. In place of DP 38-45 poly(vinylbenzylchloride), a 38-45 DPpoly(vinylbenzylbromide) prepared by polymerizing vinylbenzylbromide, isemployed as precursor polymer.

B. In place of DP 38-45 poly(vinylbenzylchloride) an equal weight of DP10-12 poly(vinylbenzylchloride) prepared by increasing the amount ofinitiator is employed as precursor polymer.

C. and D. In place of DP 38-45 poly(vinylbenzylchloride) equal weightsof DP 100-125 and DP 300-350 poly(vinylbenzylchloride) are employed asprecursor polymer.

E.-L. In place of DP 38-45 poly(vinylbenzylchloride) the followingcopolymers, prepared by free-radical copolymerizing the requisitemonomers, are used in amounts to provide 10 mmole of availablevinylbenzylchloride

    ______________________________________                                        E.    1:1 ratio  vinylbenzylchloride:styrene                                  F.    1:1 ratio  vinylbenzylchloride:butadiene                                G.    1:0.5 ratio                                                                              vinylbenzylchloride:vinylacetamide                           H.    1:1 ratio  vinylbenzylchloride:acrylamide                               I.    1:0.5 ratio                                                                              vinylbenzyldimethyloctyl ammonium-                                            chloride:4-vinylpyridine                                     J.    1:1 ratio  vinylbenzyldimethyloctyl ammonium-                                            chloride:4-vinylpyridine                                     K.    1:0.5 ratio                                                                              vinylbenzyldimethyloctyl ammonium-                                            chloride:N--vinylimidazole                                   L.    1:0.5 ratio                                                                              vinylbenzylchloride:n-dodecyl-4-vinyl                                         pyridinium chloride                                          ______________________________________                                    

FORMULATION OF ANTIMICROBIAL PREPARATIONS

The quaternary ammonium group-containing products of the Examples andIllustrative Embodiments are formulated into antimicrobial preparationsas follows:

Antimicrobial Solutions

A typical antimicrobial solution is prepared by dissolving 0.5% byweight of the product of Example I in sterile water, in a 25%/75%isopropanol/sterile water mixture, in a sterile saline solution adjustedto give isotonicity, and in an isotonic contact lens wetting solutioncontaining 1% by weight poly(vinylalcohol).

An antimicrobial cleansing composition comprising 10% of the dry polymerof Example II and 90% powdered surfactant is prepared. When thiscomposition is dissolved in water an antimicrobial solution results.

An antimicrobial salve is formulated by admixing 1% of the powder ofExample I in a pharmaceutically acceptable poly saccharride gel.

Antimicrobial Testing

The materials of Examples I, II, III, IV, V, and VI were tested forantimicrobial activity. For purposes of comparison, Zephiran® (acommerically accepted antimicrobial) and comparative materials 1, 2, and3 were also evaluated.

Two basic test methods were used.

A. Broth dilution test. Dilutions of the test materials(10,25,50,100,250 ppm) or Zephiran® (1,2,5,10,20 ppm) were prepared in10 ml nutrient broth (BBL) (NB), or trypticase soy broth (TSB),innoculated with about 10⁶ CFU/ml Pseudomonas aeruginosa 15442, andincubated at 36° C. for seven days. MIC (Minimum InhibitionConcentration) is the lowest concentration resulting in no visiblegrowth.

B. Effectiveness in saline. Test materials were added to sterile 0.9%NaCl to give 100 ppm solutions (0.01%). Zephiran® was tested at 10 and100 ppm. Tubes were innoculated with Pseudomonas aeruginosa 15442 at2.7×10⁶ CFU ml⁻¹ and incubated at 24° C. At 0.17, 0.5, 1, 2, 4, 6, 24,48 and 72 hours after innoculation a loopful (1 mm loop) was removed andtransferred to 10 ml trypticase soy broth, vortexed, and incubated at35° for up to seven days. Cidal time is the time of the first sampleshowing no growth in the recovery media.

These two tests were repeated using other bacterial strains, as well.

With the material of Example I, the results shown in Table I wereachieved. (For comparison, results with Zephiran® are given as well.

                                      TABLE I                                     __________________________________________________________________________                  Saline Test  Broth Test                                                 Test  Conc.  Cidal Time                                                                          MIC, ppm                                           Test Organism                                                                         Material                                                                            ppm    (hr.) NB     TSB                                         __________________________________________________________________________    Pseudomonas                                                                           Example                                                                             0.2    >48.00                                                                              ≧50                                                                           >100                                        aeruiginosa                                                                           I     0.5    >48.00                                                   15442         1.0    >48.00                                                                 2.0    2.00                                                                   5.0    0.50                                                                   10.0   0.50                                                                   25.0   0.17                                                                   50.0   0.17                                                                   50.0                                                                             + PG.sup.a                                                                        >48.00                                                                              >100 + PG.sup.a                                            Zephiran ®                                                                      10.0   >48.00                                                                              10-20  50                                                        25.0   1.00  --                                                               100.0  <0.50                                                                  100.0                                                                            + PG.sup.a                                                                        <0.50 ≦20 + PG.sup.a                              Staphylococcus                                                                        Example                                                                             1.0    >48.00                                                                               50    >100                                        aureus  I     5.0    48.00                                                    6538          10.0   24.00                                                                  25.0   24.00                                                                  50.0   2.00                                                                   100.0  <0.50                                                            Zephiran ®                                                                      10.0   >48.00                                                                              1       1                                                        25.0   < 0.50                                                   Escherichia                                                                           Example                                                                             1.0    2.00  <10    >10                                         coli    I     5.0    1.00                                                     8739          10.0   0.17                                                                   25.0   0.17                                                                   50.0   0.17                                                             Zephiran ®                                                                      10.0   24.00 <1      5                                                        25.0   1.00                                                     Candida Example                                                                             10.0   >48.00                                                                              <50    >50                                         albicans                                                                              I     25.0   >48.00                                                   10231         50.0   >48.00                                                                 100.0  >48.00                                                           Zephiran ®                                                                      10.0   >24.sup.L                                                                           <20    <5                                                        10.0   24.sup.S                                                               25.0   1.00                                                     __________________________________________________________________________     .sup.a polygalacturonic acid, Na salt, 200 ppm.                               .sup.L Log phase cells                                                        .sup.S Stationary phase cells                                            

The Broth test with Pseudomonas aeruginosa was repeated using othermaterials:

    ______________________________________                                                   Broth Dilution Test                                                                         Cidal Time in Saline                                 Test Material                                                                            MIC, ppm      @100 ppm (hours)                                     ______________________________________                                        Example III                                                                              >250          >48                                                  Example IV ≦50    0.17                                                 Example V  ≦100   0.6                                                  Example VI ≦250   4                                                    Comparative 1                                                                            >250          >48                                                  Comparative 2                                                                            >250          >48                                                  Comparative 3                                                                            ≧250   24                                                   ______________________________________                                    

What is claimed is:
 1. A compound having the structural formula:##STR12## wherein R is a 4 to 12 carbon atom alkyl and R' and R"independently are 1 to 4 carbon atom alkyls, X⁻ is a physiologicallyacceptable anion, q is an integer from 2 to 4 and n and m are integers,the sum of which is from 20 to 10,000 with m being from 0.2 to 0.9 timesthe sum of m plus n.
 2. The compound of claim 1 wherein R' and R" arethe same.
 3. The compound of claim 1 wherein R is hexyl and R' and R"are both methyls.
 4. The compound of claim 1 wherein R is decyl and R'and R" are both methyls.
 5. The compound of claim 1 wherein R is dodecyland R' and R" are both methyls.
 6. The compound of claim 1 wherein R isoctyl.
 7. The compound of claim 6 wherein R' and R" are both methyls. 8.The compound of claim 7 wherein q is
 2. 9. A compound having thestructural formula: ##STR13##